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Several themes and principles of behavioural neuroscience are evident in the work of Phillip Teitelbaum. He has emphasised the importance of studying behaviour in simple preparations, of re-synthesising complex behavioural patterns from these elemental 'building-blocks' and understanding their often hierarchical organisation. He also more recently has become interested in the possible power of behavioural endophenotypes. His work has resulted in a new emphasis on animal neuropsychology which is highly relevant to human psychopathology. This article illustrates these themes from examples taken from animal models of sensory neglect, drug addiction and cognitive syndromes associated with schizophrenia and other neuropsychiatric disorders., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Impulsivity is a core deficit of a number of neuropsychiatric disorders including attention-deficit hyperactivity disorder (ADHD), anti-social conduct disorder and drug addiction. Recent research has highlighted the multifaceted nature of impulsivity and the myriad of putative neural and psychological mechanisms thought to underpin behavioural syndromes of impaired self-control. Here we report a novel conceptualisation of impulsivity based on 'waiting' and 'stopping' efficiency with explanatory value in defining the psychological and neural basis of impulsivity and the high co-morbidity of brain disorders such as ADHD and drug addiction. Rats selected for high levels of impulsivity on a reaction time task analogous to the continuous performance test in humans exhibited correspondingly high levels of impulsive decision-making on a delay-of-reward task. The same rats, however, were unimpaired on a stop-signal task requiring inhibition of an already initiated motor response. The specific nature of this deficit in 'waiting impulsivity' was confirmed by unimpaired acquisition of appetitive Pavlovian conditioning, a putative ancillary measure of impulsive behaviour. These findings are significant in light of recent evidence linking impulsivity in rats to high levels of cocaine self-administration and development of compulsive cocaine seeking behaviour. We thus suggest that an inability to bridge delays to future rewards and reward-related stimuli is a candidate behavioural endophenotype that pre-disposes to clinical psychopathology.

Although amphetamine treatment has been shown to promote recovery of motor function in animals with cortical ablations, the potential therapeutic effect of amphetamine on processes other than motor control, such as attention and working memory, has been relatively unexplored. Accordingly, we investigated the beneficial effect of D-amphetamine treatment in animals with dorsal prefrontal cortex lesions (dPFC) compared with sham controls on a novel combined attention-memory task (CAM) that simultaneously measures attention to a visual stimulus and memory for that stimulus. The dPFC group was impaired in their ability to correctly detect the visual stimulus. Although this deficit occurred together with increased omissions and slow response latencies, these associated deficits largely recovered within the 10 post-operative baseline sessions revealing a selective attentional deficit in this group of animals. Nonetheless, the dPFC lesion did not substantially affect the working memory component of the task. The systemic administration of d-amphetamine served to ameliorate the attentional deficit in the dPFC group at the low dose only (0.2 mg/kg). By contrast, the dPFC group were less sensitive to the detrimental effects of the high dose (0.8 mg/kg) on any aspect of task performance. However, despite improving attention to the visual stimulus, D-amphetamine did not improve memory for that stimulus which instead appeared to deteriorate. The results provide apparently the first demonstration that low doses of D-amphetamine can ameliorate an attentional deficit in animals with selective dPFC lesions and may be a useful model of cognitive deficit in ADHD, schizophrenia or frontal brain injury.

The 'stop-signal' task measures the ability to inhibit a response that has already been initiated, i.e. the ability to stop. Human subjects who have been classified as 'impulsive', for example, those with attention-deficit/hyperactivity disorder (ADHD), are slower to react to the stop signal, and are often less sensitive to changes in the timing of signals to stop. Imaging studies have implicated fronto-striatal circuitry in the mediation of this form of response control. We report inhibition functions on the stop-signal reaction time (SSRT) task for normal rats, and following damage to the medial prefrontal cortex or to the nucleus accumbens core. Neither group of excitotoxic lesions produced significant deficits on task performance. Subsequent treatment with D-amphetamine (0.3 and 1.0mg/kg) resulted in quicker go-trial reaction times (mRT) overall, but had no significant effect on SSRT. Neither medial prefrontal cortex nor nucleus accumbens lesions had any differential effects on performance following D-amphetamine. These results are discussed with respect to the fronto-striatal circuitry involved in the mediation of behavioural inhibition.

It is becoming increasingly apparent that multiple functions of the frontal cortex such as inhibitory control and executive attention are likely sustained by its functionally distinct and interacting sub-regions but the precise localization of dissociable executive processes has proved difficult and controversial. In the present series of studies, we investigated the behavioural effects of bilateral excitotoxic lesions of different regions of the rat neocortex in the 5-choice serial reaction time task. Whereas lesions of the dorsal anterior cingulate cortex (ACC) impaired performance of the task as revealed by a reduction in discriminative accuracy, lesions made to distinct ventral regions of the frontal cortex showed selective deficits in inhibitory measures of control. Specifically, the infralimbic lesion produced increases in premature responding that was accompanied by fast response latencies. By comparison, the orbitofrontal lesion showed perseverative tendencies particularly when the inter-trial interval was made long and unpredictable, a challenge that would normally promote premature responding instead. These different behavioural effects following dorsal and ventral lesions of the rodent frontal cortex signifies the integrity of the frontal cortex in multiple executive mechanisms that work independently and complementarily by which performance is optimized. Furthermore, these data provide new insights into the functional organization of the rodent frontal cortex with a particular emphasis on localization of function.

The involvement of mesoaccumbens dopamine in adaptive learning and behaviour is unclear. For example, dopamine may act as a teaching signal to enable learning, or more generally modulate the behavioural expression, or selection, of an already-learned response. The present study investigated the involvement of the mesoaccumbens dopamine system in a fundamental form of learning: Pavlovian conditioning. In this case, the temporal association of a previously neutral visual stimulus and a biologically significant unconditioned stimulus (US), subsequently led to the production of the conditioned response (CR) of discriminated approach behaviour directed toward the conditioned stimulus (CS+), relative to a control (CS-) stimulus. 6-hydroxydopamine lesions of the nucleus accumbens (NAcc), leading to approximately 80% reductions in tissue dopamine, were made at varying time points in four experimental groups of rats, either before or subsequent to the acquisition of the CR. NAcc dopamine depletion produced long-term neuroadaptations in dopamine function 2 months after surgery, and profoundly impaired discriminated Pavlovian approach regardless of when the lesion was made. Thus, NAcc dopamine not only plays a role in conditioned behavioural activation, but also in making the appropriate discriminated response i.e. the direction of response. Further, acquisition lesions produced a far greater impact on discriminated approach than performance lesions. This difference in lesion-induced impairment implies that mesoaccumbens dopamine may play differential roles in the learning and performance of preparatory Pavlovian conditioning.

Sustained attention requires the integrity of basal forebrain cholinergic systems. The pedunculopontine tegmental nucleus (PPTg) has direct and indirect connections (via the thalamus) with the basal forebrain, suggesting that the PPTg may also play an important role in attentional processes. We examined this hypothesis by testing the effects of PPTg lesions in rats on performance in the 5-choice serial reaction time test. Bilateral lesions reduced accuracy, increased errors of omission, and increased the latency to correct responses. The deficits were more severe when neuronal damage was bilateral and concentrated in the posterior PPTg. Attentional demands of the task were increased by decreasing the stimulus duration, the stimulus brightness, or the inter-trial interval, and by introducing random bursts of white noise. These challenges impaired performance of all animals, but the magnitude of deficit was increased in the lesioned group. Conversely, lesion-induced deficits were partially alleviated when the attentional demands of the task were reduced. This pattern of results suggests that PPTg lesions produce a global deficit in attention, rather than a specific impairment in one process. The PPTg may control attentional processes through its direct projections to the forebrain cholinergic system or, indirectly, through activation of thalamocortical projections.

Previous investigations aimed at determining the role of corticopetal cholinergic afferents in cognition have relied upon human psychopharmacological studies, neuropsychological analyses of Alzheimer's patients, or psychopharmacological manipulations and excitotoxic lesions in animals. Unfortunately, each approach has its limitations. The interpretation of neuropsychological data relies upon correlations of post-mortem assessments of cholinergic degeneration that may be quite temporally distant from the time of cognitive assessment. In contrast, the use of animals allows direct manipulations of the cholinergic system and the establishment of causal relationships between acetylcholine and cognitive function but is limited by the selectivity of the toxins and drugs available to manipulate the system. The recent introduction of immunotoxins to lesion cortical cholinergic pathways with greater selectivity has allowed the effective testing of these hypotheses of cholinergic functions in cognition. Previous neuropsychological, psychopharmacological and excitotoxic lesion data are reviewed and compared to results produced using the more selective immunotoxins to provide an update to the current hypotheses of the role of corticopetal cholinergic afferents in cognitive function. Additionally, the conceptual and methodological cost and benefits of the methods of infusion used to produce lesions with these immunotoxins is assessed.

The present study assessed the behavioural sequalae of unilateral excitotoxic cortical lesions made either in the medial agranular cortex (AGm) or in the medial prefrontal cortex (mPFC) using a visual reaction time task. The task required animals to sustain a nose-poke in a central hole, until a brief light stimulus was presented in either of two holes which were located on the same side of the box: this enabled performance on each side of the rat's body to be assessed independently. Lesions of the AGm impaired performance on the contralateral side, with rats biasing their responding to the nearer of the two response locations. Analysis of the deficit revealed that rats were able to discriminate between the two stimuli and suggested that AGm lesions disrupted the control of contralateral responding. Lesions of the mPFC produced similar response-related deficits, but these were more transient in nature. Neither AGm lesions nor mPFC lesions impaired performance on the ipsilateral side, consistent with the concept of an egocentrically coded deficit.

Rats with excitotoxic lesions of the basolateral amygdala (BLA) were not impaired in the acquisition of an appetitive visuospatial conditional discrimination between stimuli varying in temporal frequency that has previously been shown to be sensitive to the effects of lesions of the striatum and cingulate cortex. After asymptotic performance was attained, discrimination was reinforced according to a fixed ratio (FR) schedule under which n presentations of sucrose were provided following n correct responses; each correct response also being reinforced immediately by a light acting as a conditioned reinforcer. Under these conditions of reinforcement when FRn=5, BLA-lesioned rats initially showed transient impairments in several aspects of performance, but rapidly attained control levels over subsequent test sessions. No further impairments occurred when FRn=10/20. However, in various conditions of extinction, further differences in performance were revealed between the BLA-lesioned and control groups, notably a significantly enhanced resistance to extinction when both sucrose and conditioned reinforcement were omitted. The results are discussed in terms of limbic-striatal mechanisms in the control of discrimination learning and the possible role of the amygdala in the mediation of different aspects of conditioned reinforcement.

The involvement of central serotonin systems in behavioural disinhibition in the rat was assessed using a symmetrically reinforced go/no-go conditional visual discrimination task. Selective central 5-HT depletion (generally averaging more than 90% in neocortex, hippocampus and striatum) was induced by intracerebroventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) following pretreatment with both a noradrenergic and dopaminergic re-uptake inhibitor. The lesioned animals failed to acquire the conditional visual discrimination. This deficit was due to an inability to withhold responding and thus correctly complete the no-go trials. The lesioned animals responded faster both correctly, during go trials, and incorrectly during no-go trials. Impulsive early responding during the initial 1.2 s of the stimulus presentation was also increased by 5-HT depletion. Subjects that were lesioned after stable performance of the task had been acquired showed a similar, but smaller effect. These animals displayed more accurate performance of the go trials, but poorer performance of the no-go trials. Once again, go trial response latencies were faster and early responses during the no-go trials were increased by the lesion. The results suggest that previous accounts of impulsive responding induced by 5-HT depletion fail to recognise the pervasive nature of this effect, which affects multiple behavioural indices of response disinhibition and can impede the acquisition and performance of discrimination tasks depending on their precise response requirements.

Three experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5-HT) on the acquisition and performance of an operant conditional discrimination in the visual modality. In the first experiment, rats with 5-HT lesions induced by infusing the neurotoxin 5,7-dihydroxytryptamine intracerebroventricularly acquired the conditional visual discrimination more rapidly than the sham-operated controls. Following acquisition, a series of manipulations of the task parameters tested the effects of the lesion on cognitive, sensory and motivational aspects of performance. In experiment two, the performance of rats that had acquired the task to asymptote before receiving lesions was assessed. The performance of this second group of serotonin-lesioned rats was similar to that of the pre-acquisition lesioned group following all but one manipulation of the task parameters. When the rate of stimulus presentations was increased, rats with forebrain 5-HT depletions were protected from the disruptive effects on performance seen in the sham-operated controls. This latter finding was also observed in a third experiment, in which the infusion of the 5-HT1A receptor partial agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), directly into the dorsal raphe nucleus improved the performance of unlesioned rats following an increase in the rate of stimulus presentations. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of serotonin function in appetitive learning and the implications for general theories of the function of serotoninergic processes in cognition.

Six experiments examined the effects of selective median (MRN)- and dorsal (DRN)-raphé nucleus lesions on the performance of the five-choice serial reaction time task. In this test rats are required to localize brief visual stimuli presented randomly in one of five locations in approximately 30 min sessions of 100 trials. Both accuracy and latency to respond are measured, as well as the incidence of premature and perseverative responding. Selective 5-HT lesions were induced by intra-raphé infusions of 5,7-dihydroxytryptamine following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. Analysis of tissue monoamine content demonstrated that the MRN lesion profoundly depleted hippocampal 5-HT (by about 90%) without affecting noradrenaline and dopamine, whereas the DRN lesion primarily depleted (by about 80%) nucleus accumbens and caudate-putamen 5-HT. Rats with 5-HT lesions of the MRN performed the task with a similar degree of accuracy to that exhibited by sham-operated controls. Although the MRN lesion did not affect the latency to respond correctly to the visual targets the lesioned animals collected the food reward significantly faster than the controls. A transient increase in the number of premature responses also resulted from this lesion. In contrast the DRN lesion produced a transient but significant increase in the accuracy of performance, and increased both the speed and the probability of responding. The similarity of the effects following global forebrain 5-HT depletion and the selective DRN lesion suggests that the 5-HT projections of the DRN rather than the MRN may play an important role in impulsive behaviour following 5-HT depletion.

The present study compared the effects of systemic 8-OH-DPAT (0.05, 0.1 and 1.0 mg/kg) with intra-raphe and intra-hippocampal infusions of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10, 30 100 ng) on delayed non-matching-to-position (DNMP) performance in rats. The highest dose of 8-OH-DPAT administered systemically impaired DNMP performance in a delay-independent manner, increased premature responding and increased response bias. Infusions of 8-OH-DPAT (100 ng) into the median raphe nucleus improved performance accuracy, independent of delay whilst having no effect on any other response measure. Infusions of 8-OH-DPAT into the dorsal raphe nucleus had no effect on performance at any dose tested. Infusions of 8-OH-DPAT into the dorsal hippocampus produced a small impairment in performance which was also independent of delay. However, this decrement in performance accuracy was not accompanied by any changes in other response measures. These findings demonstrate a dissociation between the effects of stimulation of pre- and post-synaptic 5-HT1A receptors on performance of a DNMP task although the changes in performance cannot be accounted for by changes in mnemonic function.

The current status of the cholinergic hypothesis of cognitive dysfunction in Alzheimer's disease is reviewed in the context of recent attempts to alleviate specific cognitive impairments produced in rats by excitotoxic lesions of basal forebrain neurons by treatment with cholinergic agents. AMPA-induced lesions of the nucleus basalis region in rats produce profound and relatively specific reductions in neocortical markers of cholinergic function but fail to affect performance in many tests of memory and learning in rats. However, such lesions produce specific deficits in responding accurately in a test of visual attentional performance, which are reversed dose-dependently by treatment with systemic physostigmine or nicotine. Analogous improvements have been reported in a clinical trial of the anticholinesterase tacrine in patients with Alzheimer's disease. By contrast, AMPA-induced lesions of the medial septum produce profound reductions in hippocampal acetylcholine and accompanying delay-dependent deficits in a delayed non-matching-to-position procedure which measures spatial working memory in rats. This impairment is shown to be reversed to some extent by treatment with low doses of physostigmine. The results are discussed in terms of the multivariate nature of the neurochemical pathology of Alzheimer's disease and attendant limitations in the use of the cholinergic strategy. The cognitive costs, as well as benefits, of cognitive enhancers are discussed, as well as the need to broaden our therapeutic approach to other neurotransmitter systems and other neurodegenerative disorders.

Two experiments investigated the effects of quinolinic acid induced lesions of the anterior and posterior cingulate cortices on the acquisition and performance of a conditional visual discrimination (CVD) task, in which rats were required to learn a rule of the type: "If lights are flashing FAST, press the right lever; if SLOW press left". In Experiment 1, animals with lesions of the anterior cingulate cortex (ANT group) demonstrated a significant enhancement in learning during the early stages of task acquisition. Conversely, animals with lesions of the posterior cingulate cortex (POS group) were impaired in learning during the later stages of acquisition. There were no significant differences between the ANT and POS groups on the performance of the task when either variable inter-trial intervals or reduced stimulus durations were imposed. In Experiment 2, the specificity of the lesion effects for processes operative during the early and late stages of learning was tested. Animals were trained to a criterion of 70% correct choices on two consecutive sessions prior to lesioning, and subsequently allowed to continue to acquire the task to the mean asymptotic performance level of 85% correct choices on two consecutive sessions. Animals of the POS group were impaired in learning during this later stage of task acquisition, thus replicating the pattern of results obtained in Experiment 1. The animals in Experiment 2 were then tested following a 30-day retention interval and during extinction (removal of sucrose from the magazine). The extinction test revealed an impairment in the ability of animals in the ANT group to omit lever responses in the absence of reinforcement. These results indicate that the anterior and posterior cingulate cortices are functionally dissociable, and suggest that they may form part of complementary, but competing, learning and memory systems.

The aim of the present study was to investigate the role of the cholinergic innervation of the cingulate cortex in visual attentional function and acquisition of a visual conditional discrimination task. Following AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) lesions of the vertical limb diagonal band of Broca (VDB) which provides the main cholinergic projection to cingulate cortex, animals were not significantly impaired on the 5-choice serial reaction time task. This task, which provides a continuous performance test of visual attention, has previously been shown to be sensitive to AMPA lesions of the nucleus basalis magnocellularis (nbM). In contrast to the results obtained for visual attentional function, lesions of the VDB did significantly affect the acquisition of a visual conditional discrimination. While showing a significant facilitation in the early learning stage of acquiring this task animals with lesions of the VDB were significantly impaired during the late stages of learning this task. This late learning deficit was not the result of the animals being unable to learn the task due to the presence of the lesion throughout task acquisition as the results of a second experiment revealed that when animals were pre-trained to 70% accuracy on the task and then lesioned, the impairment in late learning was still apparent. In light of the results presented in the accompanying paper (Bussey et al., Behav. Brain Res., 1996), these results suggest that the early learning effects may be due to cholinergic denervation of the anterior cingulate cortex while the late learning effects may be due to denervation of the posterior cingulate cortex. Taken together with previous work indicating a role for the nbM cholinergic system in visual attentional function, these results suggest a role for the cholinergic innervation of the cingulate cortex in conditional learning but not for continuous attentional performance.

A substantial body of literature has suggested that the memory and learning deficits associated with Alzheimer's disease are attributable to degeneration of the cholinergic magnocellular neurons of the nucleus basalis of Meynert (nbM). Subsequently, lesion-induced damage to the cholinergic projections from the nbM to the neocortex has been utilized extensively as an animal model of dementia. Ibotenic acid lesions of the basal forebrain have been found, for example, to produce deficits in a wide variety of tasks involving learning and memory. However, recently, with the availability of more potent cholinergic excitotoxins such as AMPA, it has become apparent that nbM lesions do not provide a simple animal model of the cognitive deficits in ageing and Alzheimer's disease. Further analysis suggests that many of the learning and memory impairments traditionally attributed to the cholinergic corticopetal system are due not to destruction of cholinergic neurons in the nbM, but instead result from the disruption of cortico-striatal outputs passing through the dorsal and ventral globus pallidus. Furthermore, experiments utilizing quisqualic acid and AMPA have revealed that the most convincing deficit observed as a result of such lesions is in visual attention. This role for the basal forebrain-cortical cholinergic system in attentional function is further supported by results obtained from complementary pharmacological studies. This does not exclude a role for acetylcholine in learning and memory processes. Rather, such cognitive processes appear to depend not upon the integrity of the nbM itself, but upon more rostral elements of the cholinergic basal forebrain system.

This study tested the hypothesis that the hippocampus modulates dopamine-dependent function of the nucleus accumbens using behavioural and neurochemical evidence. Rats with bilateral lesions of the hippocampus induced by colchicine and kainic acid exhibited equivalent levels of spontaneous locomotor activity but a potentiation of the hyperactivity produced, dose-dependently, by D-amphetamine measured in photo-cell activity cages. The same rats subsequently received unilateral implantations of a microdialysis probe aimed at the nucleus accumbens and showed elevated levels of extracellular dopamine in response to D-amphetamine but no significant difference in basal values in comparison with sham-operated controls. The results are discussed in terms of functional interactions between the hippocampus and nucleus accumbens involving the control of mesolimbic dopamine release.

The experiments reported here have investigated the impact on reward-related processes of lesioning the basolateral amygdala, ventral subiculum and prelimbic cortex which represent the major limbic sources of afferents to the ventral striatum. The results showed that, while lesions of the prelimbic cortex were without effect on the approach to a CS predictive of sucrose reinforcement and the acquisition of a new response with conditioned reinforcement, lesions of the other two structures significantly impaired both responses. However, there were important differences between the effects of basolateral amygdala and ventral subiculum lesions. Thus, lesions of the ventral subiculum completely abolished the locomotor response to intra-accumbens infusions of D-amphetamine, in addition to blocking the potentiative effect of the same treatment on responding with conditioned reinforcement. Lesions of the basolateral amygdala, by contrast, reduced the control over behaviour by a conditioned reinforcer, but not the potentiation of that control by intra-accumbens D-amphetamine except at the highest dose. Moreover, the locomotor response to D-amphetamine-induced increases in dopamine in the nucleus accumbens was unaffected by amygdala lesions over the dose range blocked by ventral subiculum lesions. The results suggest a rather selective effect of amygdala-ventral striatal interactions on processes subserving conditioned reinforcement and a more fundamental influence of ventral subiculum-ventral striatal interactions in mediating the psychomotor stimulant effects of D-amphetamine.

Cholecystokinin (CCK) is colocalised with dopamine in the postero-medial nucleus accumbens (NAS). We have utilised an acquisition of a new response procedure to investigate the interaction between CCK and dopamine in the control over behaviour by conditioned reinforcers. A conditioned reinforcer (CR) may be defined as an initially neutral stimulus which gains control over behaviour through selective association with a primary reinforcer. Here, rats learned to associate a light/noise compound stimulus with the imminent availability of 10% sucrose reinforcement. Later, in the absence of sucrose, responding on one of two novel levers (the CR lever) was acquired and maintained by contingent presentation of the CR alone, while responding on the second lever had no programmed consequences. In Expt. 1, infusion of 10 micrograms D-amphetamine within the postero-medial NAS enhanced responding selectively on the CR lever. Infusion of sulphated CCK octapeptide (CCK: 1 or 10 ng) alone within the same area had no effect on response rate. However, infusion of CCK immediately prior to D-amphetamine caused a dose-dependent potentiation of the impact of D-amphetamine upon rates of response on the CR lever. In Expt. 2, infusion of D-amphetamine (10 micrograms) within the postero-medial NAS again enhanced responding selectively upon the CR lever. Intra-accumbens infusion of CCK (10 ng), or s.c. administration of the CCKA receptor antagonist devazepide had no effect upon response rates. However, CCK again potentiated the D-amphetamine-induced increase in rates of response, and this potentiation was blocked by pretreatment with devazepide. These results are discussed in terms of the co-modulation by CCK and dopamine of the processing of reward-related stimuli within the NAS.

Rats can readily acquire conditional discriminations in which mixtures of drugs serve as compound internal discriminative stimuli. Excitotoxic lesions in the region of the nucleus basalis have been shown to impair the acquisition of conditional discriminations based upon external visual stimuli, but nothing was known about their effects on discrimination of internal stimuli. A baseline of undiscriminated bar-pressing for food reinforcers was established prior to surgery. Lesions were made by infusing either ibotenic or quisqualic acid bilaterally into the basal forebrain (the ibotenate-induced lesions had been shown previously to impair cortical cholinergic function and to produce non-specific damage). After surgery, rats were trained to discriminate effects of drug mixtures using a standard, two-bar operant conditioning procedure. The ibotenate, but not the quisqualate, lesion impaired the acquisition of a discrimination of a mixture of (+)-amphetamine plus pentobarbitone, while neither lesion impaired acquisition with a mixture of (-)-nicotine plus midazolam. The ibotenate lesions also reduced overall rates of responding in both experiments. Thus, the deficit in the acquisition of drug discrimination in rats with ibotenate lesions had some pharmacological specificity, but could not be related easily to disturbances in neocortical cholinergic function. In comparisons with other published data, the results suggest a possible dichotomy in the processing of interoceptive and external information in the basal forebrain, a major target of ventral striatal overflow.

Rats were reared from weaning either in isolation or in social groups for 12 weeks. Potential isolation-related changes in L- and N-type voltage-sensitive calcium channels (VSCCs) were assessed by the in vitro binding of [3H]isradipine (100 pM) and [125I]omega-conotoxin GVIA (4 pM) to membranes prepared from three discrete central nervous system regions: frontal cortex, caudate nucleus and hippocampus. The [3H]isradipine binding was generally not affected by isolation. However, [125I]omega-conotoxin GVIA binding was significantly higher in frontal cortex (52%) and caudate nucleus (75%) of isolated rats when compared with socially reared controls. The increased [125I]omega-conotoxin GVIA binding reflected an elevated density of binding sites without an alteration of receptor affinity. The possible contribution of an increased density of neuronal N-VSCCs (as labeled with [125I]omega-conotoxin GVIA) to the behavioral and neurochemical changes observed in 'isolation syndrome' is discussed.

The effects of discrete bilateral ibotenic acid lesions to 3 areas of striatum were examined on a conditional visual discrimination task involving temporal frequency (SLOW vs FAST flashes) that had previously been shown to be sensitive to the effects of dorsal striatal dopamine depletion. Two of the groups, namely, those with nucleus accumbens (ACC) and lateral caudate-putamen (LCP) lesions, were very disrupted in the acquisition of the task. The nature of the respective impairments of the 2 groups was dissociable, however. The performance of the ACC group could be improved either by manipulations of stimulus duration or inter-stimulus interval, implying an attentional deficit. In contrast, the rats with lesions of the LCP were not significantly improved by any of the behavioural challenges. Their performance was characterised by a bias to respond to the SLOW discriminandum. Under conditions of non-reward, the LCP group extinguished their responding at a similar rate to control rats whereas the ACC group were very much more persistent. Lesions of the medial caudate-putamen failed to affect any index of performance significantly. These data suggest that the LCP is necessary for the acquisition of arbitrary stimulus-response rules and that damage to an equivalent area in humans, such as in Huntington's disease, may explain deficits of procedural memory. The second part of the experiment investigated the effects of ACC lesions on established performance of the schedule. The lesioned group behaved identically to the ACC group that had been lesioned prior to acquisition, both in terms of accuracy and degree of persistence in extinction, further implying the role of attentional factors and inflexibility in the lesion-induced deficit.

Three experiments investigated the effects of primarily cortical or hypothalamic noradrenaline depletion on aversive conditioning of explicit and contextual stimuli in rats. In Expt. 1, two groups of rats were trained to respond under a variable interval schedule for food reward. One group of rats subsequently received injections of 6-hydroxydopamine into the dorsal noradrenergic bundle, resulting in profound depletion of cortical noradrenaline; the second group received vehicle injections. All rats were exposed to 5 pairings of an auditory stimulus (CS) and footshock (UCS) in a distinctive environment (the dark chamber of a place preference apparatus). During testing in a separate, neutral environment, DNAB-lesioned rats suppressed responding for food reward, in the presence of the aversive CS, to a greater degree than controls. Lesioned rats also showed a greater aversion to the distinctive environment in which they were shocked. In contrast, plasma corticosterone concentrations, measured immediately following each of these behavioural tests, revealed no differences between DNAB-lesioned and control rats. Expt. 2 showed that the DNAB lesion did not affect habituation to the light chamber of the place preference apparatus used in Expt. 1. Expt. 3 showed that 6-OHDA injection into the ventral noradrenergic bundle component of the central tegmental tract, which damages primarily the noradrenergic innervation of hypothalamus, had no effect on either behavioural or endocrine responses to conditioned aversive, explicit or contextual cues. The results are discussed in relation to other reports of the effects of DNAB lesions on simple associative learning in an aversive context.

Isolation-reared rats were compared to those reared in social groups on the acquisition of a conditional visual discrimination (Expt. I), a simultaneous (simple) light/dark discrimination and serial reversal learning (Expt. II). In Expt. I, rats reared in social isolation made more errors during the acquisition of the conditional discrimination but did reach a level of accurate performance which was comparable with that of socially-reared rats. Discrimination performance in isolates was less disruptable by manipulations of the task requirements. Reducing the number of stimulus lights or the introduction of a distracting stimulus increased the number of errors committed by socially-reared rats but did not significantly affect accuracy in isolates. Performance in isolated rats was also remarkably resistant to changes in motivational variables. Isolates responded more frequently during conditions of extinction and were virtually unaffected by pre-feeding prior to testing. In Expt. II, isolation-reared rats were not impaired in the acquisition of a simultaneous discrimination but unlike socially-reared rats isolates failed to show improvement with successive reversals of this discrimination. Isolates exhibited stronger position habits than socially-reared rats following reversal of the contingencies. These results of these two experiments combined have demonstrated a specific impairment in rule learning in isolates. Isolated rats were not impaired on a simultaneous discrimination in which accurate performance can be achieved simply by approaching the stimulus associated with reinforcement, but performed worse than controls on both the conditional discrimination and on serial reversal learning, another form of conditional task. In both of these latter tasks each stimulus becomes equally associated with reward and therefore performance can be improved by learning a rule. Post-mortem neurochemical measurements made at the completion of Expt. II revealed selective alterations in dopaminergic, serotoninergic and cholinergic markers in isolated rats. Correlational analyses indicated specific relationships between neurochemical and behavioural measurements.

A series of 4 experiments tested the effects of central catecholamine depletion on acquisition of an escape response in a spatial water maze. In Expt. 1, local infusions of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DNAB) enhanced efficient acquisition of the spatial water maze in a stressful condition (cold water), but had no effect in warm water. In Expt. 2, lesions of the ventral noradrenergic bundle did not affect acquisition of the maze, indicating that the changes observed in Expt. 1 were unlikely to have been the result of incidental damage to the noradrenergic innervation of the hypothalamus. Measures of core body temperature and plasma corticosterone were taken in parallel with the behavioral experiments and revealed that central noradrenaline (NA) depletion did not alter these responses to cold or warm water swims. Expt. 3 revealed a contrasting pattern of effects following dopamine (DA) depletion from the caudate-putamen: swimming speed was reduced in warm, but not cold water and maze acquisition was impaired, to an equal extent in warm and cold water. Finally, in Expt. 4, rats with 6-OHDA lesions of the DNAB were impaired in discriminating local cues in a simultaneous visual discrimination water maze. These results support the hypothesis that ceruleo-cortical NA depletion broadens the span of attention, particularly under stressful circumstances. In contrast, the results also indicate that striatal DA depletion mainly affects vigour of responding, as measured by swim speed, and that this effect can be reversed by the stressful effects of cold water.

Three experiments compared the effects of dopamine depletion from the caudate-putamen (CAUD; dorsal striatum) or nucleus accumbens septi (NAS; ventral striatum), or a systemically administered dopamine receptor antagonist (alpha-flupenthixol) on the acquisition and performance of a conditional discrimination task involving temporal frequency. In Expt. 1, rats receiving 6-hydroxydopamine (6-OHDA) lesions of the CAUD were impaired in the acquisition of a visual version of the task, and rats with 6-OHDA lesions of the NAS were not reliably impaired. Even when the rats with CAUD lesions had acquired the discrimination, they were still significantly slower to collect earned food pellets. Both CAUD and NAS lesions reduced a bias to respond to the faster of the two discriminative stimuli. In Expt. 2, rats with 6-OHDA lesions of CAUD were markedly impaired in their accuracy and speed of responding when they had been trained to criterion preoperatively. These effects could not be mimicked in controls by prefeeding (which had only minor effects on performance). Rats with 6-OHDA-induced lesions of the NAS were unimpaired in either visual or auditory discrimination performance, but were slower to extinguish responding than controls. In Expt. 3, alpha-flupenthixol (0.1-0.56 mg/kg, i.p.) produced dose-dependent impairments in both latency to respond and choice accuracy in visual and auditory versions of the task. In conjunction with other results, these data suggest that (1) dopamine receptor blockade and central dopamine depletion can impair discrimination performance under certain conditions (2) dopamine depletion from the ventral and dorsal striatum, respectively, have dissociable effects on behaviour controlled by conditioned reinforcers and discriminative stimuli and (3) the disruption of discrimination performance by dorsal striatal dopamine depletion is probably attributable to several factors.

Using measures of locomotor activity and stereotypy, dose-response curves to several psychomotor stimulant drugs were obtained on rats reared in deprived or normal environments. At both 0.5 and 1.5 mg/kg d-amphetamine, the deprived rats exhibited more intense stereotyped behavior than the control rats. At 5.0 mg/kg, both groups showed maximum response. However, there was no significant difference between the two groups in locomotor response. A similar pattern of results was found for pipradrol, cocaine, and apomorphine. The findings show that different social and environmental experience can modify the response to dopaminergic stimulating agents. The results also suggest that stereotyped behavior should not be considered on the same continuum as locomotor activity. These two behaviors may be mediated by different mechanisms.

Rats with ibotenic acid lesions of the nucleus accumbens (N. Acc) were studied in two spatial learning paradigms: a T-maze and a Morris water maze. Learning of a spatial discrimination task and its reversal in the T-maze were disrupted by the N. Acc lesions. As both original and reversal learning were impaired, there was no evidence of a specific lesion effect on reversal learning. The lesioned rats did not perseverate excessively in their choice of the previously reinforced arm. There was evidence of behavioural inflexibility during extinction when the lesioned rats failed to slow the pace at which they ran the maze in the absence of reward. Spontaneous alternation was not significantly affected by the lesion. Acquisition of the second spatial task, locating the hidden platform in the Morris water maze, was also impaired. The lesioned rats did eventually learn the task and successfully reached the platform with similar latencies and heading errors to controls. Thus, the N. Acc lesion impaired but did not abolish spatial learning in the T-maze and the water maze. The deficits observed in this study may reflect a role for the N. Acc in the reorganisation of behaviour in response to external change.

This experiment reports a novel means of measuring the effect of unilateral striatal dopamine (DA) depletion on co-ordinated motor behaviour involving skilled forepaw use in rats. Hungry rats were trained to use their forepaws to remove small food pellets from a moving conveyor belt. Behaviour was scored by counting successful retrievals, attempted retrievals and omissions. The rats were trained to a stable baseline, and the forepaw which they used most accurately was determined over a period of 300 trials. 6-Hydroxydopamine (6-OHDA, 8 micrograms base in 2 microliters vehicle (ascorbic acid/0.9% saline) was injected unilaterally into the head of the caudate nucleus to produce selective DA depletion, either ipsi- or contralateral to the preferred paw. A control group received vehicle alone. There was a significant change in paw use in the 6-OHDA treated rats, but not in the controls, even though accuracy was affected similarly in both sham and lesioned groups. Ipsilaterally injected rats showed increased use of the preferred paw (90% pre-operation to 98% post-operation, while contralaterally injected rats showed reduce use (86% pre-operation to 49% post-operation). These changes appeared on the first day postsurgery and were still present 3 months later.

In conclusion, DNAB lesions have been shown to have two, apparently contradictory effects in a food preference test: to increase neophobia to a novel environment, and to increase the tendency to eat novel food in a novel environment. It has been suggested that these two effects occur because, although NA has a common action on neuronal firing in terminal fields, the dissociable consequences reflect the different functions of areas in receipt of these noradrenergic afferents. In addition, it has been shown that DNAB lesions, VNAB lesions, and a benzodiazepine, chlordiazepoxide, all have somewhat different behavioral effects in the food preference test. Taken together with the lack of correlation between the various behavioral measures used in these experiments, this suggests that neophobia does not reflect a single behavioral process, such as anxiety, or reactivity to novelty.

Three experiments were performed to examine the effects of noradrenaline (NA) depletion, using 3 different methods: lesions of the dorsal noradrenergic bundle (DB) with 6-hydroxydopamine (6-OHDA), lesions induced by neonatal treatment with 6-OHDA and lesions induced by systemic DSP4 upon latent inhibition, using the taste-aversion learning procedure. NA depleted and control (sham, vehicle or saline) rats were given pre-exposure trials to either novel saccharin or to novel saccharin in a novel type of drinking bottle (the noisy bottle). Later, during conditioning trials saccharin was presented in the noisy bottles for all the rats, followed by lithium chloride injections. Saccharin aversions, tested for in the noisy bottles, indicated considerably weaker saccharin aversions (i.e. more latent inhibition) by the control groups pre-exposed to both saccharin and the noisy bottles. These context-dependent latent inhibition effects were clearly attenuated by all 3 treatments that depleted central NA. Biochemical assays confirmed the NA depletions in each case. The results, demonstrating the intimate role of central NA neurons in contextual control of latent inhibition in taste-aversion learning, appear to conform with current attentional theories of NA function in the forebrain.

Five experiments examined the effects of destruction of the dorsal noradrenergic bundle (DNAB), arising in the locus coeruleus, both on brightness and spatial visual discrimination, and selective attention. An analogue o Leonard's 5-choice serial reaction task for human subjects was used. Hungry rats were trained to detect brief (0.5 sec) flashes of light presented randomly in one of 5 locations with a fixed intertrial interval of 5 sec, paced by the rat. Correct responses were rewarded with food and incorrect responses punished by time-out (darkness + delay). Following training to high levels of accuracy (80%, with less than 20% errors of omission), rats received either 6-OHDA (4 micrograms/2 microliters) injected bilaterally into the trajectory of the dorsal bundle, or injection of vehicle (0.1% ascorbic acid in 0.9% saline). The 6-OHDA lesion was sufficient to reduce cortical NA by 84%. Performance on both the spatial discrimination and brightness (produced by graded reductions in the brightness of the stimuli) discrimination was unaffected by DNAB lesions. However, the DNAB lesion produced significant decreases in accuracy and increases in omissions when the stimuli were presented at faster, unpredictable rates. In addition, although intense white noise failed to produce differential impairments when presented simultaneously with the visual discriminanda, the DNAB lesion significantly impaired accuracy when the noise was presented immediately prior to, but not overlapping, the onset of the visual stimuli. The implications of this pattern of deficits in performance found following DNAB lesions is discussed in terms of disruptive effects of cortical NA depletion upon mechanisms of selective attention and arousal.

Rats received infusions of ibotenic acid into the substantia innominata, in the region of the nucleus basalis of Meynert (nbM), before and after training on simple (simultaneous) and conditional visual discriminations. The ibotenate infusions reduced cortical choline acetyltransferase (ChAT) levels by about 20%, destroyed many ChAT-immunoreactive neurons in the nbM, but also caused the loss of many neurons in the substantia innominata and adjacent areas. These lesions did not impair the acquisition and performance of a simple visual discrimination, but did impair reversal of the discrimination and the performance of a conditional visual discrimination. However, the degree of impairment was unrelated to the degree of cortical ChAT loss. Ibotenic acid lesions to the dorsal globus pallidus also impaired reversal of discrimination but left acquisition and performance unaffected. Striatal dopamine depletion produced by 6-hydroxydopamine (6-OHDA) infusions into the mid-ventral caudate nucleus impaired performance of the simultaneous visual discrimination. Cortical noradrenaline depletion produced by 6-OHDA lesions of the dorsal noradrenergic bundle either alone or in combination with ibotenic acid lesions of the substantia innominata had no effect on acquisition of the discrimination. It is concluded that ibotenic acid lesions of the substantia innominata or to the dorsal globus pallidus affect learning and performance of conditional visual discrimination performance and impair reversal learning without affecting the capacity to discriminate visual events. These results are compared to those following cortical noradrenaline depletion or striatal dopamine loss.

Two experiments examined the effects of excitotoxic lesions of the substantia innominata on cholinergic activity in the neocortex and on performance in a paradigm measuring selective attention in the rat. In Expt. 1, ibotenate-induced lesions produced approximately 30% reductions in cortical choline acetyltransferase (ChAT) activity, and damage to wide regions of the substantia innominata and ventral pallidum. The rats were impaired in their ability to localize brief visual targets in a serial reaction time task, as measured by reduced choice accuracy. This impairment was particularly evident at short stimulus durations, but the lesioned rats did not exhibit evidence of primary visual sensory dysfunction and exhibited only minor deficits when the stimuli were presented unpredictably. The deficit was exacerbated when distracting white noise was interpolated into the task. The rats with lesions were also slower to respond correctly, probably resulting partly from the adoption of a speed/error trade-off strategy, and were slower to collect earned food pellets, although they made no more errors of omission than controls. In Expt. 2, quisqualate-induced lesions produced fewer signs of non-specific damage and 50% reductions in cortical ChAT activity. This lesion produced generally qualitatively similar, but weaker effects to those of ibotenate-induced lesions. It was notable that many of the deficits following either ibotenate- or quisqualate-induced lesions lasted for several months after surgery. The results are discussed in terms of the cholinergic hypothesis of cognitive dysfunction. It is argued that lesions of the substantia innominata, including the magnocellular cholinergic neurons of the nucleus basalis of Meynert, produce deficits in attentional processing, which may not result from damage specifically to cholinergic cells. However, the longevity of the effects makes these preparations suitable for further exploration of the restorative effects of cholinergic treatments.

Six experiments examined the effects of 6-hydroxydopamine (6-OHDA) induced lesions of the nucleus accumbens septi (NAS) on performance of a spatial discrimination. The behavioral paradigm used was an analogue of Leonard's 5-choice serial reaction time task for humans. The 6-OHDA lesion produced an 87% depletion of dopamine (DA) in the NAS, only a minor (25%) depletion of DA in the anterior caudate, and a 75% depletion of neocortical noradrenaline (NA). The lesion transiently attenuated both the speed and impulsivity of responding on the baseline schedule, but did not affect discriminative accuracy. In addition, the lesion attenuated the increase in premature responding caused by both systemic administration of D-amphetamine and bursts of loud white noise, presented just prior to the onset of the visual discriminanda. However, the lesion did not affect discriminative accuracy in these 2 conditions. The lesion also only had extremely minor effects on performance of this paradigm when the intertrial intervals were unpredictable. These results contrast with the previously reported pattern of behavioral effects resulting from forebrain NA depletion in the same behavioral paradigm. They therefore complete a double dissociation of effects on accuracy and vigour of responding, supporting theories of a division of arousal-type processes.

Rats were trained to orient to a visual cue presented in either visual field. An asymmetry in reaction time showed that they used one eye to control responses to both visual fields. Cortical removal contralateral to this dominant eye produced a severe and permanent response deficit. Cortical removal ipsilateral to the dominant eye caused a mild and temporary change. Thus, in the rat, there is a functional lateralization that is similar to that seen in humans.

The relationship between schedule-induced polydipsia (SIP) and pituitary-adrenal activity in rats was investigated using two different approaches that involved either capitalizing on pre-existing individual differences in the propensity to show SIP, or by inducing differences in plasma corticosterone by behavioral or pharmacological means. Thus, in Expt. 1, SIP was monitored after corticosterone levels were pharmacologically altered with drugs that act at the benzodiazepine receptor. In Expt. 2, the relationship between individual differences in water consumption during SIP and plasma corticosterone levels was determined. In addition, corticosterone levels were determined after the prevention of drinking during SIP. Results indicated an inverse relationship between plasma corticosterone levels and SIP. It was also found that corticosterone levels were significantly higher following SIP with water available than after SIP without water. The implications of these results for previous hypotheses of SIP are discussed.

A 6-hydroxydopamine-induced lesion of the dorsal noradrenergic bundle (DNB) in rats markedly decreased neocortical noradrenaline concentration (NNC) by 72-100% as measured 1, 3 and 13 months after the lesioning procedure. The concomitant assessment of neocortical alpha 2- and beta 1-adrenoceptor binding (NAAB and NBAB, respectively) usually indicated significant increases of 25-72% for these two variables. There were, however, cases of unchanged NAAB and NBAB which presumably reflected an incomplete DNB lesion and a consequent time-related, partial recovery of NNC. The results emphasize the potential for long-term sequelae of the DNB lesion, and the existence of a critical NNC threshold (approximately 10-30% of control NNC values) which modulates postsynaptic alpha 2- and beta 1-adrenoceptor density.